Background: Angiopoietin-like 4 (Angptl4) is a secreted protein involved in triacylglycerol homeostasis. Results: Angptl4 was required for fasting, glucocorticoids, and catecholamines to stimulate cAMP-dependent signaling and triacylglycerol hydrolysis in murine fat, a response reproduced by treating adipocytes with purified ANGPTL4. Conclusion: Angptl4 is a physiological mediator of lipolysis. Significance: This finding may impact aberrant lipolytic states like insulin resistance.